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A good friend recently pointed out his surprise at my use of the word communist in this post, given my political leanings. He’s right; that wasn’t the right word. What I meant was totalitarian. I do think that the cells in our body are locked in a kind of communism, but the negative aspect I was pointing out isn’t necessarily linked to that. Obviously, communism has lead to totalitarianism often, but I hope it’s clear from my blogs that hyper-individuality in the midst of society has its serious costs as well. We’ve seen the cost of extreme individuality in the stock market (no surprise, from a historical perspective; it’s all right there in Marx), and we see its costs in cancer.

The experiment of America, of Federalism, is partly about grappling with these seemingly incongruous interests. The Founders tried to find a solution, and the Transcendentalists tried to find a solution. But so did the Bolsheviks. And so does Polistes, and so does Dictyostelium, and so do all living things. For social creatures, negotiating the individual and the group is an everlasting struggle of life.

This conflict plays out in our bodies as well, at times. That was the only message I intended.

An interesting article appeared in the NY Times a couple of days ago. I have my doubts about the general appeal of a rap performance about evolutionary biology, but maybe it’s great. Who knows? You can investigate Baba Brinkman’s “The Rap Guide to Evolution” for yourself here and here.

Of particular interest, the article highlights one part of the show:

Dictyostelium is notorious, in some circles, for its strange life-style. Usually, an individual Dictyostelium lives alone as a single cell. But when food is scarce, the single cells come together and form a being known as “the slug”; this crawls off in search of better conditions. When it finds them, the slug develops into a stalked fruiting body, and releases spores. But here’s the mystery: not all members of the slug get to make spores — and thereby contribute to the next generation — so why do they cooperate?

Dictyostelium is an incredibly interesting group of organisms. A genus of usually solitary, single-celled amoebae, members of the group are also facultatively social. Individual Dictyostelium cells spend most of their life on the forest floor, eating bacteria. When bacteria become scarce, and the amoeba cells start to starve, they release chemical pulses that draw individual cells together. Once together, the cells form a mound of cells, all piled on top of each other. And then something amazing happens, the mound starts to crawl (yes, crawl) as one unit, across the forest floor. This slug is now, by any reasonable definition, a multicellular individual.

A beautiful image of a Dictyostelium discoideum slugs (bottom) and stalks with spore masses on top. Photo credit: Owen Gilbert

But that’s not the end of this startling story. After crawling away a bit (and by the bye, these slugs are visible and you can watch them crawl), cells at the leading edge organize themselves into a stalk, a pillar, via which the lagging cells in the slug will eventually ascend. The stalk cells die, and the other cells crawl up the stalk and become a mass of sporulating cells, leaving clonal offspring that might disperse from the impoverished environment more easily because of the (slight) height. (Well, in fact, this particular sequence is not universal. Some species of Dictyostelium do it differently, but the ultimate product, the formation of a slug and stalked spore body, is the same).

The comparison to wasp workers and queens is clear enough, but the comparison to our bodies is even clearer. Dictyostelium is a group with sterile worker cells and reproductive cells, and the group is composed of genetically identical cells ( . . . well, sometimes). We are a group of cells with sterile workers cells (our soma, all of our tissues and body parts) and reproductive cells (our germ, egg and sperm). The only difference (and it’s a big one, admittedly) is that our worker cell caste has differentiated into many subcastes—different sterile cell types and tissues composed of sterile cells—just like the workers of highly social wasps.

So Dictyostelium is sort of like Polistes: it has cycles of solitary and social, and it bridges the gap between completely selfish and altruist. (In fact, some of the most important work on Dictyostelium comes from the lab of two former(-ish) social wasp researchers). Given this, the next time someone tells you there are no transitionary intermediates that reveal major shifts in evolution, you can point them to Dictyostelium.

So the question: Why do Dictyostelium cells seemingly willingly, suicidally sacrifice themselves, forgo reproduction, and form the structure (the tissue) that is the stalk? The same question applies to worker wasps, and the cells in your finger. The beginings of the answer were provided by Darwin, but the mathematical framework wasn’t worked out for just over a century later, by über-famous social wasp researcher Bill Hamilton. Hamilton’s insight was as simple as it was brilliant.

It goes like this. Imagine an individual I will call the actor. The actor has two reproductive choices: She can reproduce directly by having her own offspring (thus leaving her genes and heritable tendencies, including her tendency to reproduce directly), or she can reproduce indirectly by assisting relatives have enough additional offspring such that they compensate for our actor’s sacrifice in direct reproduction. This works because relatives share genes. So, for example, our actor (let’s assume she’s a human now) could have one child, or help a sister have two additional children (over the children her sister would normally have absent our actor’s help). Because our actor and her sister share genes by descent, in each case, the same amount of genes are left by the our actor. If the actor has one child, she leaves half of her genes to the next generation. If the actor helps her sister have two additional offspring—because she’s related to her full sister by half, and thus related to her nieces and nephews by one quarter—then our actor leaves two times one quarter of her genes, or half, the same as if our actor had one child directly.

Some individuals in populations will have heritable tendencies for direct reproduction (the selfish tendency). Others (due to natural variation) will have heritable tendencies for indirect reproduction (essentially, helping, or being a worker, an altruist). Whichever individuals actually reproduce more, leaving more copies of their genes—including their heritable tendencies for either selfish direct reproduction or altruist indirect reproduction . . . whichever tendency happens to leave the most genes to the next generation will become more common, generation after generation. The other tendency will wane. Either tendency could be more successful, and this can change depending on other external, environmental factors. But whatever the context, if being a sterile helper results in more genes’ being shuttled into the next generation, that tendency will evolve. And the same goes for the tendency for direct reproduction. Neither tendency is universally better. Natural selection decides.

In Dictyostelium, this calculus is simplified, because the cells are (often) all clones of one another, so if one cell reproduces directly or by helping a clone reproduce, the reproductive success to each cell is the same. In this context, conflict-free cooperation can much more easily evolve. Of course, I’ve already pointed out in previous blogs that mutation can strike, and change the behavior of a cell, just like in our bodies. When this happens, the happy harmony is disrupted, and the cheater cell might corrupt the system by reproducing wildly, or otherwise refusing to engage the social contract. This happens in Dictyostelium, just as it does in us. All social systems have cheaters, cancer.

The harmony of Dictyostelium can also be disrupted when slugs are composed of genetically different cells, or even (sometimes) different species. When this happens, cells don’t easily sacrifice themselves and become stalk tissue. It’s easy to see why that behavior might not be favored by natural selection. In this context, becoming a sterile worker might mean very little or no indirect reproduction (for example, if the spores are all distant relatives of the stalk cell). If sterility and helping leave no genes indirectly, the behavior washes away over generations. The only tendencies that are left are the selfish: In a mixed group, fight for direct reproduction or perish. So, this generates great conflict, and individual cells in the slug try to position themselves such that they will be in the spore mass.

Because of this kind of conflict, it was long ago predicted that members of social groups should be able to recognize close relatives. Since that prediction—a prediction that derives directly from the mathematical evolutionary framework I describe above—many social creatures have been shown to recognize kin. You might think this kind of conflict (from genetically distinct cells) has little bearing on humans, but it’s exactly the kind of conflict that stem cell transplants can generate. The potential for that conflict is playing itself out in me now. My new cells have kin recognition abilities, and if they aren’t tricked into thinking my body is kin, a significant conflict may erupt.

So now, I’m like a mixed colony of Dictyostelium. Having hopefully exterminated the mutant cheater cancer cells, I now face yet another other social conflict. As time passes, the probability of that conflict rises.

I’ve received a somewhat strong response to my last post, which is great. Keep the comments and email coming. Regarding that post, many have questioned my final comment about sympathy for my cancer. To be sure, I chose that word to be provocative, but I do have sympathy for all life that is marked for extermination (in this case, by my hand). I have sympathy for the forest that is clear-cut, and I have sympathy for the cattle that we grow to kill and eat. Of course these organisms are not trying to kill me, so naturally my sympathy is greater for them. But I don’t think my cancer is trying to kill me either.

Natural selection dictates that those that are more adept at doing whatever allows them to leave more offspring will be more common in future generations. If their reproductive advantage is heritable, then the traits that allowed them to be more numerous will also be more and more common in the population over time. Imagining, again, that our bodies are a colony of cells, or a nest of wasps, or a school of fish, or whatever, then it’s easy to see why slowly reproducing individuals or individuals that don’t reproduce at all will become less and less numerous over time relative to a rapidly reproducing member of the same group. I thought I’d made clear the restricted sense in which I invoked that term, sympathy.

Looking back, perhaps I could’ve been clearer, but that’s the nature of blogging. The arguments are made mostly extemporaneously, a kind of stream of consciousness. The entire work is presented piecemeal, across days, and new entries sometimes only make sense in light of previous posts. Plus my chief editor is on permanent leave. (Actually, Greg helps a lot with editing.) So I will clarify (or retort) a bit. I don’t mean to criticize any who have responded. (We normally live in Vermont, where I think criticism of what others have said is illegal). I’m just reassertingclarifying my view for the enjoyable dialogue.

When I first read some of the objections, the situation reminded me of a conversation I once had with a Physician’s Assistant who was at the time coring a hole in my ileum for bone marrow. During that delightful visit, we had a chat. At one point, I made some comment along the lines of what I’ve been saying here: The cancer cells are just doing their thing, trying to stay alive, like any creature. Stunned, he looked at me at asserted, “But cancer is bad.” I thought about his short sentence for a long time, and given the context of our conversation, he could only have meant one thing: Cancer is morally bad. Now, don’t get me wrong. He wasn’t suggesting that I had cancer because of my moral failings or past-life no-nos (although I’m amazed at how many do believe such things, and will actually tell me about it to my face). He meant that the cancer itself was evil. You know, just like how wolves are evil for eating cute bunnies.

I now get it that some of you thought that I had written the wrong word, intending instead to say empathy. The substance of the post shows my empathy for my cancer, certainly. I just wanted to express something else for the life that I am desperately trying to kill. That life is not evil; I just find myself in conflict with it.

Obviously, I hate (and I mean that word, too) that I have cancer. I often say (usually to poke fun at the bright-siders) that the only thing I’ve learned from cancer is that I don’t want to have it. I want each and every cell destroyed. Why else would I have endured four years of off-and-on therapy, with the last two years’ mostly futile treatments being virtually continuous. Just because I know the cancer cells are not trying to kill me does not mean I will relent in trying, by any means necessary, to kill them. Self-preservation trumps sympathy.

I invite dissent and alternate perspectives. I’m not doing this just to get my ideas out there; I hope to learn something from this blogging experience too. But I did say what I meant. Just because I have some sympathy for my cancer doesn’t mean I want to help it or keep it as a pet. Who didn’t have sympathy and cry for Ol’ Yeller? But that diseased, frothing mongrel still had to die.

Okay, I know. I didn’t actually blog again last night. Sorry for that, but since I’ve been feeling so, so, so much better, I’ve begun to realize just how much work I was laying aside. I’ve been catching up.

So as a mini-catchup, I’ll offer this symbol and some thoughts:

Polistes in Thoreau's attic

This is a nest of the genus Polistes—from the attic of the home where Henry David Thoreau was born. (Really. You’ll just have to trust me on this, okay?) Greg and I visited Walden Pond and toured Concord with expert historian Joseph Wheeler (grandfather of a good friend of ours, and son of the historian Ruth R. Wheeler, author of Concord: Climate for Freedom) just before I was admitted for my stem cell transplant, over seven weeks ago.

My greatest intellectual influences, without a doubt, come from the 1800s. Marx, Engels, Darwin, Kropotkin, Emerson, Whitman, and of course Thoreau. Like millions of other American High School students, I was especially influenced by the Transcendentalists. But unlike some of my other 19th Century influences, the Transcendentalists—and especially Thoreau, I think—were caught in a kind of struggle. They all wanted to forge a better world, and they all believed in cooperative alliances and effort; many joined communes and similar groups. But the Transcendentalists were also great advocates of the individual, and the individual spirit. This is especially true of Thoreau, who famously retreated from society, lived alone for a few years, and even went to jail in solitary protest against slavery. At the same time, his writings and his message influenced Gandhi and MLK to reshape society through coordinated group action. Thoreau is like Polistes.

Polistes is a one of the varieties of wasp I discussed in an earlier post, the kind in which groups of females, all able to have offspring, initially fight to become the egg layer and queen of the colony. There is little-to-no physical evidence of division of labor—no obvious anatomical queen and worker castes. Eventually, the losers in combat settle down, sort of, and become workers. But the social group is composed of would-be individualists, biding their time for an opportunity to shrug off their worker roll and take the queen’s throne. It is a group that exhibits cycles of social behavior interrupted by periods of solitary behavior. Polistes are the Transcendentalists of the wasp world, symbolically bridging the gap between selfish and altruist, individual and group.

This is how I see Thoreau. For humans as individuals, this might be a good, stable state. For wasps, it’s unclear to me. For the colony of cells in our bodies, such conflict is decidedly unwelcome—and when it happens, we call it cancer.

But are our individual cells slave to some purely communisttotalitarian‡ society? Why wouldn’t they “prefer” individuality, a notion so decidedly American? Does our body’s proper functioning demand that our worker cells (that form our kidney’s, lungs, livers, and, of course, blood) be oppressively chained to a social contract that forces them into a single roll (despite having all the genes needed to perform any roll), never allows them to reproduce freely (many are unable to divide after a point, and all are restricted), and then ultimately commit suicide (apoptosis) when the group so decides? What a dystopian nightmare!

So, as strange as it may sound, from a perspective of freedom, and rejoicing in the individual at all levels—ideas that ignited my intellect and set me on a path to activism and my current study so many years ago—I have sympathy for my cancer. I cannot blame those cells for wanting to be free.

Solitary wasps, like most animals, live their life . . . well, in solitude. Except to mate, they tend to stay away from other members of their own species. Some build small nests for their young, and some provide a modicum of parental care—the first steps toward social habit—but they do not live together in groups.

Social wasp colonies come in a variety of flavors. Some are composed of tentatively co-existing individuals, and little cooperation happens, except to share a nest. Some social wasps join together to make a group, and they fight to see who gets to be the queen. The one that wins gets to lay eggs, subjugates the others, and the others often try relentlessly to overthrow her rule; they want to lay eggs too, and they have the ovaries to do so, but they often just settle for being a worker, a forager, a builder—and if they lay an egg or two, it’s surreptitiously. I think it’s easy to see that this is a rather unstable social group, and even in these groups there are cycles of social behavior interrupted with solitary behavior. Both social and solitary interests are obvious.

Other social wasps are more interconnected. Some wasps in Central and South America (including Apoica) form large colonies of individuals who cooperate extremely well. In this derived situation, the worker wasps are much more numerous, and they now run the show—they subjugate the queens, often kicking potential or undesirable queens out of the nest. And the workers are workers, forever. They can’t lay eggs. (They just don’t have developed ovaries; there are exceptions of course, but in general, they don’t.) Only the queens have the properly developed organs needed to lay eggs. Here, we see the first permanent and most fundamental subdivision of labor necessary for stable social habit: The division of labor between the reproductives and the sterile workers.

The workers often come in different shapes and sizes; the queen differs from them. These differently equipped sterile workers work—they defend the nest; they forage for food, water and wood, which they macerate into pulp for the nest; they repair damage; they build new parts; they feed the young; and they dispose of the dead. The queen does none of these. Well, in some instances she may initiate the paper cells into which she lays the eggs, but other than that, she lays eggs and does little more.

None of these wasps are ever alone; when the colony gets too big, a group of queens and a group of workers, and rarely a small cohort of males (the workers are all female) fly to a new site and begin a new nest. The solitary life has been completely abandoned; the division of labor has made sure of that. These wasps are almost certainly locked, or approaching being locked, into sociality. The queen doesn’t forage and the workers all work. They have specialized so much that reversal to the solitary habit would be difficult . . . but it does happen.

Rogue wasps defy the structure and reverse in their behavior to the ancestral, the solitary. They eat food, take resources, enjoy protection, and contribute nothing. Sometimes they are outright aggressive (recall, solitary wasps don’t like to be around others). They lay eggs (against the rules), and their offspring may inherit their tendencies. They are commonly called “cheaters,” because they don’t keep the social compact. They often lose in their mission that if unchecked could disrupt the entire social system. They are ejected, or killed by other workers. But sometimes, their rogue efforts go unchecked, and the entire colony then can be at risk of collapse. Because they shrug off their roll as worker (no doubt due to a random mutation), and reject the division of labor upon which the colony is based, the entire system can fail.

Other wasps have taken these divisions of labor even further. In some hornets, for example, preliminary evidence suggests that the larvae of the nests, the young, are the only individuals who can digest food. The adults feed the larvae, and the larvae feed back to the adults digested vomit and spit. If the adults are separated from the larvae, they die of starvation.

This work, ongoing in my lab, is preliminary, as I said, but intriguing if true. This would mean that the genes to digest food (which they all have) have been silenced in the adults, and only the workers express those genes and have those proteins and enzymes. The larvae have become workers of a new and specialized type. They have become the digesters of the colony. They have become the stomach. Division of labor has arrived at a new, extreme level: the development of tissues, organs.

So why am I writing about all of this? Partly, of course, because this is the stuff I think about all the time: wasps, and the transition for solitary to social. But I see clear connections to our bodies, and to cancer. My view is not novel, to be sure, but for me it is comforting, in a way.

Each of us is a giant colony of intimately cooperating individual cells. They all descend from a single cell. At the first division, they could separate and go their own way, like bacteria do all the time. But they don’t, at least not usually. Sometimes this is exactly what happens. A very good friend of mine was in the early stages of pregnancy years ago, before I knew her. It isn’t clear exactly what happened, but something like this is plausible: At some point during the early stages, an unfertilized egg, or the embryo’s cells, or some cell incurred a random mutation. The mutation caused the cell to revert to its ancestral, primitive instincts. That one cell shrugged off the social contract and started dividing without control. The cells would divide and go their own way, just like their ancestral bacterial brethren, with no cooperative instinct remaining. In other words, one of the embryonic cells became a “cheater” in the social contract. It didn’t play its roll, take its position as a worker, or as they are commonly called, a differentiated cell type. The cheater had the potential to destroy the entire colony, my friend. In wasps, these mutants are called “cheaters.” When it happens in us, we call it cancer. (My friend has been cancer-free for years, thanks to chemotherapy.)

But usually, the cells all stay in line. They don’t divide and go their own way; they divide, and stay, and differentiate into tissues—various subcastes of the worker caste. Once we’re born, these cells do various things: they defend the body; they distribute food; they repair damage; they build new parts; and they dispose with the dead. The sex cells do none of these. Sound familiar?

For my cancer, the correspondence is crystal clear. In my case, the particular mutation that occurred was demonstrated genetically. In my case two of my chromosomes in a single cell physically crossed over on another. And when the crossing over occurred, the top part of one chromosome was attached to the bottom of the other, and vice versa. This is a common enough occurrence, especially for germ, or sex cells (you know, our queen caste). But in this case, when this happened, a particular gene, named bcl-2, was placed in contact with a so-called hyper-promoterenhancer‡—a region of DNA that controls the expression, the copy rate, of a gene. Bcl-2 makes a protein, and placed next to this hyper-promoterenhancer, it started making a lot of this protein.

This particular protein—from an ancient gene that we share with nearly all cellular life—in multi-cellular organisms controls a phenomenon seen in their cells called apoptosis, programmed cell death. Programmed cell death is a fundamental part of the social contract of our bodies, our apoikas of individual cells. In such a group environment, cells can’t divide without end, and they can’t stay forever. Cells must die sometimes, and make way for other cells, else the group of cells—our bodies—may have problems.

And here was the crux of my problem. The more bcl-2 that is expressed, the more easily a cell can resist signals to kill itself. So in me, when bcl-2 started being hyper-expressed in that one cell, it became immortal. And with that, the social contract was broken, and the cell started off on its own way, dividing and giving to all its daughter cells the same tendencies. As this social cheater continued to pursue its selfish interest, the whole colony—my body—started having problems. And I got sick, as those immortal daughters became so numerous that they began to clog up passageways, organs, and vessels.

This is the natural history of my cancer, follicular b-cell lymphoma, the best example that proves cancer cells are nothing more than cheater wasps at the nest. From their perspective (that is, from a selection standpoint), being freed from programmed cell death ain’t a bad thing at all. Individuals that leave more offspring win, right? This cell was on Logan’s Run . . . and having lots of babies at the same time. The problem is, all those cells that are (were?) in my body don’t have global knowledge, and so they don’t realize that they are sealing their own fate: If the colony dies, so do they, in this case. There is no complete reversal to the free-living single cell. We’ve evolved too far for that. Or have we . . . (more on that later).

This is my view. I just wanted to share it. I am comforted by it, because I understand the how and the why of my cancer. I have never once asked “Why is God doing this to me?” That’s just never been in my head. I know why I have cancer, and I understand that the cancer cells in my body—once freed from the social contract—are just like bacterial invaders. They are trying to make their way, and reproduce, like all other creatures. It’s simply an unavoidable consequence of nature.

‡UPDATE: The distinction between a promoter and an enhancer is subtle, and I won’t go into it here. But I needed to correct it, because in an attempt to write generally, what I wrote was technically incorrect.